Project Summary The failure of experimental therapeutics for Alzheimer?s disease (AD) in clinical studies emphasizes the need for novel therapeutic targets with novel mechanisms of action. One strategy is to look to the body?s natural defense mechanisms. Postmortem studies of AD patients and aged-matched controls have confounded researchers for years with evidence of known pathological markers of AD in control groups with lack of cognitive impairments. Rather than asking if elevated beta-amyloid and neurofibrillary tangles are detrimental for neuronal function and survival, since this has collectively and repeatedly been demonstrated, a more interesting question is, ?Why do many individuals have normal cognition, despite these pathological abnormalities?? The norepinephrine (NE) system is a key modulator of cognitive function, neuroinflammation and the systemic immune system. Severe degeneration of NE neurons in AD patients may underlie disease progression at many levels. Adrenergic receptors on microglia regulate neuroinflammation and govern protective mechanisms for neuronal function and survival. Migration of peripheral immune cells to the brain is also regulated by NE tone and may be impaired in AD patients. Using a platform of established learning and memory paradigms, transgenic models of mice overexpressing human mutant amyloid precursor protein (APP+ mice) or human mutant tau protein (PS19 mice), and chemogenetic tools to selectively downmodulate the NE system with restoration of tone at specific beta adrenergic 1 and 2 receptor subtypes (ADRB1 and ADRB2), this proposal will determine the role of noradrenergic receptor subtypes in AD-like cognitive deficits, neuroinflammation, and pathology. Subsequent experiments will examine functional consequences of conditional KO of ADRB1 or ADRB2 in myeloid lineage cells (e.g., microglia and macrophages, but not neurons), first in an acute LPS model of neuroinflammation, and then on pathology, neuroinflammation and behavior in the 5XFAD mouse model of AD. An in vitro culture platform will examine molecular mechanisms through which adrenergic agonists modulate inflammation in response to LPS or oligomeric amyloid beta in isolated primary microglia cultures from transgenic mice with conditional KO of ADRB1 or ADRB2. A final set of studies will determine the role of recruitment of peripheral monocytes to the brain in prevention of AD-related pathology and cognitive deficits and will determine the contribution of NE tone at ADRB1 and ADRB2 on this recruitment. These final studies will use cutting edge technology for enriching or depleting peripheral immune cell populations, combined with previously described behavioral platforms, chemogenetic tools for targeted downmodulation of NE tone, and innovative flow cytometry analysis of brain, blood, spleen and bone marrow to identify effects of modulation of NE tone on resident microglia, systemic immune cells and recruitment of systemic immune cells to the brain. The results obtained here will increase our knowledge about the role of the adrenergic system in modulation of cognition and central and peripheral inflammation and will lead to identification of novel mechanistic pathways to modulate these functions in neurodegenerative disorders.